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使用亲和选择-质谱检测选识别一流的小分子卡结合剂

Ashraf N Abdo, Hossam Nada, Moustafa Gabr

bioRxiv : the preprint server for biology

|November 24, 2025

概括

研究人员确定了第一个与阿尔茨海默病进展相关的蛋白质CAPON结合的小分子MA32. 这一发现为开发针对这种以前未被探索的蛋白质标的向疗法开辟了新的途径.

科学领域:

神经科学是一个神经科学.
药理学药理学是指药理学的学科.
生物化学生物化学

背景情况:

神经元氧化合成酶 (nNOS) 适应蛋白 (CAPON) 与阿尔茨海默病的进展有关.
卡普恩是阿尔茨海默病的未经探索但有前途的治疗点.

研究的目的:

评估CAPON作为治疗点的化学处理能力.
使用高通量选方法识别与CAPON结合的小分子.

主要方法:

亲和选择质谱法 (AS-MS) 用于选大约10,000个小分子的CAPON结合.
使用Dianthus平台评估结合相互作用并排除自光或灭效应.
微尺度热泳 (MST) 用于选择化合物的定量亲和度的确定.

主要成果:

AS-MS确定了52种最初的化合物与CAPON结合.
五种化合物进行了进一步的验证,MA32的解离常数 (Kd) 为74μM.
MA32是第一个通过AS-MS识别为CAPON的结合剂的小分子.

结论:

这项研究成功地建立了针对新型蛋白质点的小分子发现工作流.
MA32代表了开发针对阿尔茨海默病的CAPON向治疗的重要起点.
这些发现证实了CAPON作为一种可用药的目标,并为未来的药物发现工作提供了基础.

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